Chronic myeloid leukemia (CML) results from transformation of a primitive hematopoietic cell by the BCR-ABL gene. The BCR-ABL tyrosine kinase (TK) inhibitor imatinib is highly effective in inducing remissions and improving survival in CML patients but does not eradicate primitive malignant hematopoietic stem and progenitor cells (HSPC), which persist in CML patients in remission on imatinib. Therefore patients need continued treatment to maintain remission and may be at risk for relapse. In the preceding grant period we have extensively investigated mechanisms of response and resistance of CML progenitors to imatinib. Our results indicate that imatinib and BCR-ABL TK inhibitors, including dasatinib and nilotinib, effectively inhibit BCR-ABL TK activity in CML progenitors and markedly inhibit progenitor proliferation, but induce only modest increase in apoptosis. Quiescent CML progenitors are particularly resistant to apoptosis following imatinib treatment. Persistence of CML HSPC despite effective BCR-ABL TK inhibition indicates the need for additional strategies to enhance elimination of malignant stem cells. We have shown that CML progenitors-treated with imatinib and other BCR-ABL TK inhibitors continue to be responsive to microenvironmental growth signals that help maintain their viability.
In Specific Aim 1 will further investigate the role of microenvironmental interactions in resistance of CML hematopoietic stem cells to apoptosis following imatinib treatment using in vitro stromal co-coculture and in vivo mouse models of CML. We will investigate whether the a4b1 integrins and N-cadherin adhesion receptors contribute to protection of CML HSPC by the microenvironment. We will also investigate the role of Wnt-?-catenin signaling in CML stem cell maintenance following imatinib treatment. We have found that treatment with the histone deacetylase (HDAC) inhibitor LAQ824 in combination with imatinib results in significantly increased apoptosis of CML CD34+ cells, which is associated with markedly reduced expression of the anti-apoptotic protein Mcl-1.
In Specific Aim 2 we will further investigate whether HDAC inhibitors can selectively and effectively induce apoptosis and eliminate CML HSPC in combination with imatinib, and will investigate mechanisms of apoptotic targeting of CML HSPC. We will investigate the mechanisms of Mcl-1 inhibition and the role of Mcl-1 downregulation in mediating HDAC effects on CML HSPC. We will also identify and investigate additional HDAC-inhibitor induced alterations in gene regulation that may lead to enhanced apoptotic targeting of CML HSPC using chromatin immunoprecipitation and gene expression array based approaches. Successful completion of these studies is expected to lead to future clinical application of these approaches to eliminate leukemia stem cells and potentially achieve cure in CML patients.

Public Health Relevance

The BCR-ABL kinase inhibitor imatinib is highly effective in inducing remissions and improving survival in chronic myeloid leukemia (CML) patients but does not eradicate primitive leukemia stem and progenitor cells. Therefore patients need continued treatment to maintain remission and may be at risk for relapse and additional methods to enhance elimination of CML stem cells are required. The studies proposed here will investigate mechanisms of protection of leukemia stem cells from elimination by imatinib and examine whether blocking these mechanisms will enhance their elimination. The results if these studies will have direct application to clinical approaches to eliminate leukemia stem cells and potentially achieve cure in CML patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095684-08
Application #
8020120
Study Section
Special Emphasis Panel (ZRG1-HEME-D (02))
Program Officer
Merritt, William D
Project Start
2002-02-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
8
Fiscal Year
2011
Total Cost
$310,971
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Irvine, David A; Zhang, Bin; Kinstrie, Ross et al. (2016) Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep 6:25476
Qi, Jing; Singh, Sandeep; Hua, Wei-Kai et al. (2015) HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation. Cell Stem Cell 17:597-610
Li, Ling; Bhatia, Ravi (2015) Role of SIRT1 in the growth and regulation of normal hematopoietic and leukemia stem cells. Curr Opin Hematol 22:324-9
Wang, Li-Sheng; Li, Ling; Li, Liang et al. (2015) MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors. Blood 125:1302-13
Wang, Zhiqiang; Liu, Zheng; Wu, Xiwei et al. (2014) ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired resistance. PLoS Genet 10:e1004414
Li, Ling; Osdal, Tereza; Ho, Yinwei et al. (2014) SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells. Cell Stem Cell 15:431-46
Kuo, Ya-Huei; Bhatia, Ravi (2014) Pushing the limits: defeating leukemia stem cells by depleting telomerase. Cell Stem Cell 15:673-5
Gallipoli, Paolo; Cook, Amy; Rhodes, Susan et al. (2014) JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood 124:1492-501
Gallipoli, Paolo; Pellicano, Francesca; Morrison, Heather et al. (2013) Autocrine TNF-α production supports CML stem and progenitor cell survival and enhances their proliferation. Blood 122:3335-9
Wang, Z; Yuan, H; Roth, M et al. (2013) SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells. Oncogene 32:589-98

Showing the most recent 10 out of 34 publications